Abstract
KMT2A (formerly MLL) gene rearrangements are common and clinically significant in acute leukemias, with outcomes influenced by the fusion partner. Over 100 fusion partners are known, but new ones continue to emerge. This study identified three novel partners-myocardin-related transcription factor B (MRTFB), sorbin and SH3 domain-containing 1 (SORBS1), and scavenger receptor cysteine-rich family member with 5 domains (SSC5D)-in pediatric and adult acute leukemia cases. Three cases were analyzed: a boy with B-cell precursor acute lymphoblastic leukemia, a girl with acute myelomonocytic leukemia, and a woman with therapy-related acute myeloid leukemia (AML). Diagnostics included cytogenetic analysis, fluorescence in situ hybridization (FISH), multiplex reverse transcription-polymerase chain reaction (RT-PCR), whole genome sequencing (WGS), and confirmation of breakpoints by Sanger sequencing, with validation at DNA and RNA levels, using patient-specific primers. WGS identified three novel in-frame fusions: KMT2A::MRTFB, KMT2A::SORBS1, and KMT2A::SSC5D, all within the major KMT2A breakpoint region. All patients achieved complete remission with tailored therapy, including chemotherapy and hematopoietic stem cell transplantation where indicated. Follow-up demonstrated durable remissions ranging from 9 to 23 months at the time of reporting. This study expands the catalog of KMT2A fusion partners, highlighting MRTFB, SORBS1, and SSC5D as novel leukemia-associated genes. The findings underscore the value of WGS for comprehensive detection of rare genetic events, enabling improved molecular classification and prognostic assessment in KMT2A-rearranged leukemias.